Thomsen_1988_J.Pharmacol.Exp.Ther_247_635

Three groups of rats were used to examine the basis for tolerance development to chronic exposure to diisopropylfluorophosphate (DFP). One group was injected every 3 days with a low dose of DFP (referred to as DFP1); the second group was similarly injected with a higher dose of DFP (referred to as DFP2) and a third group that served as a control was injected with the diluent, arachis oil. Symptoms of intoxication were mild in DFP1 animals. DFP2 animals initially exhibited severe symptoms of DFP poisoning. However, by the fifth injection, symptoms were mild and it was concluded that the animals had become tolerant to DFP. Animals were sacrificed 24 hr after injection 1, 2 or 7. Acetylcholinesterase activity was depressed in both groups throughout the period of DFP administration. EPPs and MEPPs were recorded from the hemidiaphragm cut muscle preparation to monitor quantal release, binomial statistical parameters of release and spontaneous transmitter release. No significant changes in MEPP amplitude were observed. MEPP frequency was significantly depressed in both groups of DFP-treated animals. When stimulated at 50 Hz the second EPP of the train was significantly depressed relative to the first EPP in the DFP2-treated animals during the initial period of treatment. Quantal release and statistical release measurements were not affected by DFP treatment. The EPP duration was significantly increased in DFP1- and DFP2-treated animals. In DFP2-treated animals that had become tolerant to DFP, the EPP duration had shortened. It is concluded that tolerance development to chronic treatment with DFP is not associated with changes in presynaptic activity or changes in postsynaptic sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)